非酒精性脂肪肝病（NAFLD）是指无过量饮酒史而出现肝细胞脂肪变性和脂质贮积等特征的临床病理综合征，但其发病机制尚未完全阐明。研究表明组蛋白去乙酰化酶SIRT1和HDAC3参与NAFLD发生，我们前期结果显示NAFLD患者肝脏中组蛋白去乙酰化酶9（HDAC9）的表达水平明显上升，体外过表达HDAC9导致脂滴明显增大，并促进脂肪酸合成关键酶的活性增加，提示HDAC9在NAFLD以及肝脏脂代谢调控中发挥重要的作用。本项目拟使用脂肪肝病动物模型ob/ob小鼠，HDAC9肝脏过表达以及敲除小鼠，通过分析各项生理学指标，确定HDAC9在肝脏脂代谢中的作用。进一步在肝细胞中分析HDAC9对各种脂代谢物质流以及关键基因表达及活性的影响，同时寻找与HDAC9相互作用蛋白，结合体内外实验确定HDAC9调节肝脏脂代谢的分子机制，最后在临床标本中验证HDAC9和NAFLD相关性，为NAFLD的治疗提供新靶点。

Nonalcoholic fatty liver disease (NAFLD) refers to the presence of hepatic steatosis, as demonstrated by imaging or histology, in the absence of significant alcohol consumption or other known secondary causes. However, the precise pathogenesis of NAFLD is not fully understood. It has been reported HDACs, SIRT1 and HDAC3, play a critical role in occurrence of NAFLD. The preliminary results of our study showed that a significantly increased HDAC9 expression level in liver biopsies of NAFLD patients. Overexpressed HDAC9 in hepatic cells increased hepatic lipid accumulation and the activities of hepatic enzymes involved in fatty acid synthesis. These results indicated that HDAC9 protein may play an important role in regulating occurrence of NAFLD and hepatic lipid metabolism. In this project, we will use ob/ob mouse and HDAC9 overexpressed and knockout mouse as model systems to investigate the physiological role of HDAC9 in regulating hepatic lipid metabolism. We will further analyze the effects of HDAC9 on the metabonomics flux of lipid metabolism, expression and activity of key genes, and find interacting protein of HDAC9 in overexpression or knockdown of HDAC9 in hepatocytes. We will combine in vivo and in vitro results to reveal the physiological function and molecular mechanism of HDAC9 on hepatic lipid metabolism and NAFLD, then, verify the correlation between HDAC9 and NAFLD in clinical specimens, thus provide new insight of regulatory network of NAFLD and new target for prevention and treatment of NAFLD and metabolic syndrome.